The development of novel approaches to the treatment of non-melanoma skin cancer is of significance. Non-melanotic skin cancers are by far the most prevalent malignancy in the US, comprising about half of all other cancers combined. Basal cell carcinomas (BCCs) are the overwhelming majority of skin malignancies. Our experience and that of others shows that ALA-PDT can have efficacy comparable to ordinary surgery and is advantageous in the skin because it provides enhanced selectivity, outstanding cosmesis, and the option of treating multiple lesions and large surface areas, particularly for nevoid BCC syndrome (NBCCS) patients or those with complex or multiple lesions. However it has reduced overall efficacy, can be painful and relatively ineffective for thick lesions. Therefore the overall goal of this project is to understand the underlying mechanisms in order to improve the efficacy of ALA-PDT, without compromising its selectivity and cosmetic benefits. In the current funding period we have shown, that recurrence basal cell carcinoma (BCC) can be minimized by high light doses at high irradiances, and that PDT treatment efficiency can be greatly improved and pain virtually eliminated at low irradiances. This has led to the hypothesis that elucidation of the low irradiance fluence-tumor response relationship is critical for optimizing efficacy of PDT. PDT can be compromised by vasospasm that locally limits oxygenation, and by inhomogeneous distributions of photosensitizer within the tumor. We hypothesize that examination of perfusion and intra-tumor vascular and photosensitizer distributions is critical for choosing appropriate treatment strategies, understanding mechanisms and constructing computational models for PDT. In collaboration with Project III, we have demonstrated for the first time that PDT enhances patient immune reactivity to a BCC-associated tumor antigen. Pre-clinical studies in Project III have shown that PDT enhanced anti-tumor immunity can be further augmented by addition of an immune modulating agent. We hypothesize that ALA-PDT induced immune responses improve clinical outcomes and can be augmented by the addition of immune modulators, and that vaccination with PDT-treated cells will treat existing BCC and prevent new carcinomas. Finally, we have shown that PDT efficacy can be improved in pre-clinical models through the addition of agents that potentiate effects of oxidative intracellular damage and inhibit tumor growth. We hypothesize that these agents will also improve clinical outcomes with topical and systemic photosensitizers.

Public Health Relevance

Clinical PDT has developed with little attention to, or understanding of the effects of treatment parameters on selectivity and outcomes. We have shown the fundamental importance of irradiance on both selectivity and outcome, and also on host responses. Work in the last funding period has discovered real-time metrics that can be used to select appropriate treatment parameters. The information derived from the proposed work will not only benefit skin cancer, but also may lead to paradigm shifts in the approach to clinical PDT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055791-19
Application #
8376643
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
19
Fiscal Year
2012
Total Cost
$364,120
Indirect Cost
$143,038
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Shafirstein, Gal; Battoo, Athar; Harris, Kassem et al. (2016) Photodynamic Therapy of Non-Small Cell Lung Cancer. Narrative Review and Future Directions. Ann Am Thorac Soc 13:265-75
Shafirstein, Gal; Rigual, Nestor R; Arshad, Hassan et al. (2016) Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study. Head Neck 38 Suppl 1:E377-83
James, Nadine S; Joshi, Penny; Ohulchanskyy, Tymish Y et al. (2016) Photosensitizer (PS)-cyanine dye (CD) conjugates: Impact of the linkers joining the PS and CD moieties and their orientation in tumor-uptake and photodynamic therapy (PDT). Eur J Med Chem 122:770-85
Brackett, Craig M; Kojouharov, Bojidar; Veith, Jean et al. (2016) Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis. Proc Natl Acad Sci U S A 113:E874-83
Dhillon, Samjot Singh; Demmy, Todd L; Yendamuri, Sai et al. (2016) A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non-Small Cell Carcinoma In Situ or Non-Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study. J Thorac Oncol 11:234-41
Rohrbach, Daniel J; Rigual, Nestor; Arshad, Hassan et al. (2016) Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma. J Biomed Opt 21:18002
Jenkins, Samir V; Srivatsan, Avinash; Reynolds, Kimberly Y et al. (2016) Understanding the interactions between porphyrin-containing photosensitizers and polymer-coated nanoparticles in model biological environments. J Colloid Interface Sci 461:225-31
Patel, Nayan J; Chen, Yihui; Joshi, Penny et al. (2016) Effect of Metalation on Porphyrin-Based Bifunctional Agents in Tumor Imaging and Photodynamic Therapy. Bioconjug Chem 27:667-80
Baran, Timothy M (2016) Recovery of optical properties using interstitial cylindrical diffusers as source and detector fibers. J Biomed Opt 21:77001
Ito, Fumito; Ku, Amy W; Bucsek, Mark J et al. (2015) Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer. PLoS One 10:e0143370

Showing the most recent 10 out of 157 publications